1. Field of the Invention
This invention relates to compounds which inhibit histone deacetylase (HDAC) enzymatic activity. This invention is also directed to pharmaceutical compositions comprising such compounds as well as to their use to treat conditions, particularly proliferative conditions, mediated at least in part by HDAC.
2. References
The following publications are cited in this application as superscript numbers:    1 Marks, et al., Nature Reviews: Cancer 1:194-202 (2001)    2 Finnin, et al., Nature, 401:188-193 (1999)    3 Geerts, et al., European Patent Application Publication No. 0 827 742, published Mar. 11, 1998
All of the above publications are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
3. State of the Art
In all eukaryotic cells, genomic DNA in chromatin associates with histones to form nucleosomes. Each nucleosome consists of a protein octamer made up of two copies of each histone: H2A, H2B, H3 and H4. DNA winds around this protein core, with the basic amino acids of the histones interacting with the negatively charged phosphate groups of the DNA. The most common posttranslational modification of these core histones is the reversible acetylation of the ε-amino groups of conserved highly basic N-terminal lysine residues. The steady state of histone acetylation is established by the dynamic equilibrium between competing histone acetyltransferase(s) and histone deacetylase(s) herein referred to as HDAC. Histone acetylation and deacetylation has long been linked to transcriptional control. The recent cloning of the genes encoding different histone acetyltransferases and histone deacetylases provides a possible explanation for the relationship between histone acetylation and transcriptional control. The reversible acetylation of histones can result in chromatin remodeling and as such act as a control mechanism for gene transcription. In general, hyperacetylation of histones facilitates gene expression, whereas histone deacetylation is correlated with transcriptional repression. Histone acetyltransferases were shown to act as transcriptional coactivators, whereas deacetylases were found to belong to transcriptional repression pathways.
The dynamic equilibrium between histone acetylation and deacetylation is essential for normal cell growth. Inhibition of histone deacetylation results in cell cycle arrest, cellular differentiation, apoptosis and reversal of the transformed phenotype. Therefore, HDAC inhibitors can have great therapeutic potential in the treatment of cell proliferative diseases or conditions.1 
The study of inhibitors of histone deacetylases (HDAC) indicates that indeed these enzymes play an important role in cell proliferation and differentiation. The inhibitor Trichostatin A (TSA) causes cell cycle arrest at both the G1 and G2 phases, reverts the transformed phenotype of different cell lines, and induces differentiation of Friend leukemia cells and others. TSA and sub-roylanilide hydroxamic acid (SAHA) have been reported to inhibit cell growth, induce terminal differentiation, and prevent formation of tumors in mice.2 
Trichostatin A has also been reported to be useful in the treatment of fibrosis, e.g., liver fibrosis and liver chirrhosis.3 
In view of the above, there is an ongoing need for inhibitors/antagonists of HDAC.